Catheter-based ultrasound transducers

ABSTRACT

A multi-angular ultrasound device. Multi-angular ablation patterns are achieved by a catheter based ultrasound transducer having a plurality of transducer zones.

STATEMENT OF GOVERNMENT INTEREST

Some work described herein supported by the National Cancer Institute(National Institutes of Health, Bethesda, Md.) under NIH GrantR44CA134169 and Grant R44CA112852. The United States Government may havecertain rights in inventions described herein.

FIELD OF THE INVENTION

The present invention generally relates ultrasound treatment,specifically ultrasound thermal therapy.

BACKGROUND OF THE INVENTION

Thermal therapy has been widely investigated as an alternative tosurgical procedures for treatment of diseased tissue. Minimally invasivecatheter based high-intensity ultrasound has been investigated in depthby a few groups for treatment of diseased tissue. Such technology hasthe benefit of targeting the treatment location accurately with theleast minimal invasive procedure. Moreover, large ablation tissuevolumes can be achieved with single insertion. The applicability of suchtechnology improves drastically with the capability of accuratelyproducing multi-angular ablation patterns. Multi-angular ablationpatterns can be produced to result in treating the diseased tissuewithout damaging the nearby healthy tissue.

Researchers have investigated the use of single direction elementtransurethral ultrasound applicator to treat prostate cancer and ablatedthe prostate by rotating the applicator. By using tubular transducers,such ablation can be produced without rotating the applicator. Byexciting different sectors with different frequency and power in amulti-sectored tubular ultrasound transducer, many distinct beampatterns can be obtained. Designing different geometries of the sectoredtransducer can produce various ablation patterns. The frequency of theelement and the input power can be used to change the depth ofpenetration of the ultrasound wave into the tissue and thus control theablated tissue volume. Computational modeling can provide optimizeddesign parameters to design multi-sectored tubular transducersefficiently for specific ablation pattern. Previous studies have showngood agreement between experimental and simulation results obtained fromfinite element analysis of bio-heat equation.

Among the many types of disorders and diseases that have beeninvestigated for possible treatment by ultrasound, Stress urinaryincontinence (SUI) is one of the most common. SUI is the most commontype of urinary incontinence symptomatic in 15 million adult women inthe US. Risk factors for SUI include advancing age, childbirth, smokingand obesity. Conditions that cause chronic coughing, such as chronicbronchitis and asthma, may also increase the risk and/or severity ofsymptoms of stress incontinence. SUI is defined by the InternationalContinence Society as “leakage on effort, exertion, sneezing, orcoughing”. In normal condition, the endopelvic fascia provides supportto the female urethra. Typically, damage to this structure (e.g.,childbirth) weakens that support, rendering the urethra and sphincterless able to resist normal pelvic forces, allowing the urethra todistend and urine leakage.

Treatment options range from pharmaceuticals, surgical procedures, andthermal therapies. Pharmaceuticals are the primary physician directedtreatment, representing $1.2 billion in annual expenditures in 2005.Pharmaceuticals and pads do not provide permanent relief, but impose aconstant economic drain with undesirable physical and quality of lifeside-effects. Injecting bulking agents to treat SUI showed bothobjective and subjective improvements. Presently, the syntheticmidurethral sling, inserted via a retropubic or transobturator is thedefacto gold standard for surgical treatment of SUI. In theseprocedures, a sheet of material is placed between the urethra andvagina, and attached at both ends to the pubis. This “sling” or“hammock” effectively replicates tightening of the endopelvic fascia,pulling the urethra in a superior/posterior direction, and increasingthe hydrostatic pressure required to void the bladder. Other techniquesinclude suturing the bladder neck to the back of the pubic bone. TheBurch procedure can be performed via laparoscopy with robot assistance.Synthetic midurethral sling procedures are widely performed fortreatment of female SUI, which is a simple and quick procedure with lowmorbidity. The surgical procedures are an effective treatment option,with 90% improvement rates. However, the surgical interventions requirea hospital setting with significant anesthetic intervention (typicallygeneral), as well as incisions in the vagina or the suprapubic region.Failure rates are reported in the 5% to 10% range and consist primarilyof bladder perforation, immediate post-procedure retention, infection,and de novo incontinence at some period post procedure.

The application of RF thermal therapy, similar to the approach commonlyused in orthopedic medicine to tighten joint capsules, has beeninvestigated as a surgical technique with a direct application of RFenergy and heat to tighten and remodel the endopelvic fascia. Thissurgical technique requires two 2 cm incisions within thesuperior/lateral aspects of the vagina to expose the endopelvic fasciato RF heating. This thermal shrinkage of the endopelvic fascia hasdemonstrated long term improvement rates at greater than 75%. In anotherstudy researchers showed shrinkage of endopelvic fascia (25-50%) upon RFtreatment of SUI, and observed that the tissue does not re-stretchduring the healing time. The underlying science of this approach issound as temperature elevation (55-70 C, 1-3 minutes) shrinks thecollagen by affecting the basic structure of the molecule. Wall andothers have confirmed that thermal remodeling of collagen does occur indifferent time intervals in relation to elevated temperatures. Further,the thermal insult stimulates the generation of new collagen, orneocollagenesis, to further strengthening and restore the collagenoustissues. This is the basis for using heat for ligament tightening, jointstability, and skin tightening. Minimally invasive devices, utilizingtransurethral delivered RF energy to the bladder neck region for RFremodeling of the endopelvic fascia, have been inconsistent because thephysics of RF ablation (including tissue resistivity variability) do notprovide consistent predictable application of therapeutic levels ofenergy at levels as deep as 10 mm and without causing injury to theurethra, bladder neck, or vagina.

All current surgical interventions involve incisions or needleinsertions through the urethral wall or vaginal wall, in some instancesdepositing or placing implants. RF ablation have has shown to alterconnective tissue and damage muscle in joint capsule and preserves thesynovium from damage with regeneration of synovium after 7 days ofsurgery. Lopez et al., observed that RF energy altered intermolecularinteraction between collagen molecules (alpha chains) resulting intomolecular disorganization due to thermal energy effect. In another studyresearchers showed shrinkage of endopelvic fascia upon RF treatment ofSUI. Regeneration of normal tissue was confirmed in two 6-month patientfollow-up from histological analysis. RF treatment remodeled porcinebladder neck and proximal urethra from histopathological analysis after8 weeks of survival study. The SURx RFA device treated endopelviccollagen to maximum temperature of 80° C. with significant reduction ofincontinence; it did not succeed in marketplace because it was invasiverequiring a surgical procedure (insertion of strips along fascia 1 cmlateral and 2 mm deep for entire length of urethra) and less effectivethan a hammock sling. The Renessa device required the insertion ofneedles at multiple locations (36 discrete points) primarily treatingnear the bladder neck. Results were inadequate to gain market adoption.Loss of urethral pressure from the surrounding supporting tissuesresults in SUI. Urethral support has been determined to be greatest inthe mid-region.

The potential of thermal therapy for shrinking and tightening theendopelvic fascia as a possible treatment methodology for SUI has beenclearly demonstrated; however, there is a clear need forminimally-invasive application of heating energy versus surgicalapproaches, and better more sophisticated and selective approaches oftargeting the endopelvic fascia from within the urethra are required.

SUMMARY OF THE INVENTION

One embodiment of the invention relates to Multi-zoned tubularultrasonic transducer arrays. One embodiment relates to methods of usingthese transducer configurations to achieve a multi-angular directionalablation pattern.

Additional features, advantages, and embodiments of the presentdisclosure may be set forth from consideration of the following detaileddescription, drawings, and claims. Moreover, it is to be understood thatboth the foregoing summary of the present disclosure and the followingdetailed description are exemplary and intended to provide furtherexplanation without further limiting the scope of the present disclosureclaimed.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other objects, aspects, features, and advantages ofthe disclosure will become more apparent and better understood byreferring to the following description taken in conjunction with theaccompanying drawings, in which:

FIG. 1A is a schematic of a flexible catheter based ultrasoundapplicator, FIG. 1B is a cross-sectional view of a multi-sectored arraytubular ultrasonic transducer.

FIG. 2A illustrates an applicator with thermocouples; FIG. 2Billustrates an applicator without thermocouples, and FIG. 2C illustratesa cross-section along A-A of FIG. 2B.

FIGS. 3A-B shows a bi-sectored tubular array applicators, one withbladder anchor balloon, FIG. 3A illustrates a close-up of thetransurethral cooling balloon and the bladder balloon; FIG. 3Billustrates a close-up of the transducer within the transurethralballoon.

FIG. 4 is an ultrasound ablation applicator, thermocouple on the balloonand the deployed thermocouple position on the applicator. The anchorballoon for deployment in the bladder is shown at the far right in thisfigure.

FIG. 5 shows the placement of thermocouples and the ultrasoundapplicator using the custom template. Sensors were inserted in tissue inboth active zone directions and at inactive zones with respect toangular direction.

FIG. 6 is a top view of the location of the applicator and the variousthermocouples in cross section.

FIG. 7 illustrates a computer system for use with certainimplementations.

FIG. 8 shows the acoustic intensity wave pattern generated at thesurface of the water bath for the given output acoustic power using (8A)0 Watts (no power), (8B) 6 W for a lateral angular sector, (8C) 6 W fortwo lateral angular sectors, (8D) 6 W for all three angular sectors,(8E) 6 W for all three sectors rotated ˜20 deg counterclockwise, and(8F) 6 W for two larger sectors. (The black arrows (b-e) and ovals (f)indicate the water wave pattern).

FIG. 9A Acoustic power output from the catheter based applicator foreach of two angular directions during the treatment, (9B) temperatureprofiles recorded by the thermocouple sensors during the treatment, (9C)cumulative dose calculated from each of the thermocouple readings, (9D)gross pathology of the ablated zone with scale showing the laterallinear extent of the treatment zone.

FIGS. 10A-C Smith chart of transducer impedance measurements for thelatest applicator design specifically for 10(a) sector 1, 10(b) sector 2and 10(c) sector 3. The table shows the power measurement conducted todetermine the efficiency of each sector.

FIGS. 11A-11B Photographs of ablated tissue along an axial plane throughthe central axial direction through the applicator. (11A) Temperaturecontour and tissue ablation overlay. (11B) Thermal dose contour andtissue ablation overlay. Good correspondence can be observed betweencoagulated (identified by gross discoloration) tissue andtemperature/thermal dose levels predicted by the model. Radial depth oftissue coagulation predicted by model (˜14 mm) matches well withobservations and experimental measurements.

FIGS. 12A-12D Comparison between gross tissue pathology observed duringablation of ex vivo chicken breast muscle and temperature (left), anddose (right) predicted by modeling. Cases: (12A, 12B) Acoustic power=4,4 W and time=2 min. (12C, 12D) Acoustic power=5, 5 W and exposure time=2min.

FIGS. 13A-13B Comparison between gross pathological tissue damageobserved during ablation of ex vivo chicken breast, and temperature(13A) and dose (13B) predicted by modeling. Acoustic power=7, 7, 3 W andexposure time=2 min.

FIG. 14 (a) Schematic of the Insertion of the treatment applicator withthe anchor balloon held against the bladder neck, 14(b) schematic ofdirectional ultrasound treatment procedure for SUI with respect toanatomy. (Anatomy drawing courtesy www.niddk.nih.gov), 14(c) schematicof the urethra showing the endopelvic fascia and connective tissue and14(d) schematic of normal anatomy of urethra and Its supportingstructures obtained from MR Images. [SP=symphysis pubis, V=endovaginalcoil, R=rectum, ATFP=arcus tendlneus fasclae pelvis, pu=pubourethralligament, pe=perlurethral ligament, pr=puborectal sling)

FIGS. 15A-C Oncentra contouring software platform. 15(A) Axial plane,15(B) sagittal plane, 15(C) 30 reconstruction of contoured organs.

FIG. 16 Schematic diagram to depict work flow during 30 patient specificfinite element modeling processes. Left to right: Segmentation 22 FEMMesh>Power Deposition>Thermal 3D Profile

FIG. 17 SAR patterns from two (left) and three (right) sectoredtransducers.

FIG. 18 Ablation with two sectored (90°) device sonicating with acousticpower=4.7 W

FIG. 19 Ablation with triple sectored applicator (center sector=60″).Acoustic powers=4.7, 4.7, 1.2 W

FIGS. 20A-D 3D temperature distributions obtained for a representativepatient anatomy. The bladder is shown in black, vaginal wall in mediumgrey, urethra in black wire-frame, and the applicator in dark grey.20(a) Evolution of 45° C. (gray: safety), 52° C. (light grey: necrosis)and 60° C. (dark: coagulation) over a 2 min sonication time for acousticpowers of 6-6-0 W, with perfusion of 2 kg/m³/s. 20(b) Comparison of 52°C. contours obtained after 2-min sonication at 6-6-0 acoustic watts forperfusion values of 0.5 kg/m³/s (light) and 5 kg/m³/s (dark). 20(c)Comparison of 52° C. contours obtained after 2-min sonication at 6-6-0acoustic watts (light) and 4-4-0 acoustic watts (dark), perfusion=2kg/m³/s. 20(d Comparison of 52° C. contours obtained after 2-minsonication at 6-6-0 acoustic watts at perfusion of 2 kg/ms when usingapplicator with 14 mm (light) and 10 mm (dark) long transducers. Notethe longer penetration depth, but shorter axial length for the latter.

FIG. 21 Ablation volumes obtained during 2 min sonications with maximumacoustic power of 7.05 W (10 mm transducer segment). Power weightingbetween sectors was set to 100%-25%-100% (left), 100%-50%-100% (center)and 100%-75%-100% (right). Power values to the central sector can bevaried to vary penetration depth.

FIG. 22 Tissue gross pathology and thermometry for the excised pig GUtract on the tissue holder after treatment. The graph Is each columnrefers to data from each treatment. The first, second and third rowsrefer to image of treated region, dose recorded by the deployed andballoon thermocouples, and temperature profile of the deployed andballoon thermopiles, respectively.

FIG. 23 Ultrasound imaging of the urethra through the vagina wall inpig.

FIGS. 24A-D: (a) Dissected tissue with applicator and discolored tissuedue to treatment, (b) another view of the treatment region, (c) the dosedelivered as recorded by thermocouples and (d) the temperature profilerecorded by the thermocouples.

FIG. 25 Ultrasound imaging of the urethra through the vagina wall

FIG. 26 An example treatment screen shot from ablation treatmentsoftware.

FIGS. 27A-B: Gross pathology of the (a) urethra and (b) vagina wall. Theellipses in (a) indicated the treatment regions 1, 2 and 3.

FIG. 28 Thermometry and delivered acoustic power for each of the threetreatment regions shown in FIG. 27A-B {5.2.8.} The first, second andthird columns (SUI1, SUI2 and SUI3) refers to treatment regions 1, 2 and3 respectively. Similarly the first, second and third row representsDose, Temperature and delivered Acoustic Power versus Time graphsrespectively.

FIGS. 29A-C(a) dose delivered to the tissue at both the thermocouplelocations, (b) Temperature profile of the deployed thermocouple and thethermocouple on the balloon, and (c) delivered acoustic power by all theRF channels for EWE-99 SUI2. Note that no dose was delivered at theballoon surface (i.e. at the urethral wall).

FIGS. 30A-C The average, minimum and maximum applied acoustic powersettings used for (a) Channel 1, (b) Channel 2 and (c) Channel 3 in allthe ewe experiments.

FIGS. 31A-B The average, minimum and maximum temperature recorded by the(a) deployed thermocouple, and (b) thermocouple on the balloon. (Theblack, red and blue refers to average, minimum and maximum valuesrespectively)

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In the following detailed description, reference is made to theaccompanying drawings, which form a part hereof. In the drawings,similar symbols typically identify similar components, unless contextdictates otherwise. The illustrative embodiments described in thedetailed description, drawings, and claims are not meant to be limiting.Other embodiments may be utilized, and other changes may be made,without departing from the spirit or scope of the subject matterpresented here. It will be readily understood that the aspects of thepresent disclosure, as generally described herein, and illustrated inthe figures, can be arranged, substituted, combined, and designed in awide variety of different configurations, all of which are explicitlycontemplated and made part of this disclosure.

Catheter based ultrasound ablation devices provide a minimally invasiveprocedure for thermal therapy. However, the success of such proceduresdepends on accurately delivering the thermal dose to the tissue. One ofthe main challenges of such therapy is to deliver thermal therapy at thetarget location without damaging the surrounding tissue or major vesselsand veins. To achieve such multi-directional capability, a multi-angularbeam pattern is required.

1. Multi-Sectored Ultrasonic Device

One aspect of the invention relates to a multi-sectored tubularultrasonic transducer and control the directionality of the acousticpower delivered to the tissue by each sector simultaneously. Multi-zonedtubular ultrasonic transducer arrays with three active sectors wereconstructed for proof of concept. Using these transducer configurations,a multi-angular ablation pattern was created in ex vivo chicken breasttissue as described in the Example section.

FIG. 1A illustrates a multi-sectored ultrasonic device 200. The device200 has a catheter body 210 (an embodiment of which is shown as anextruded structure in FIG. 3). A cooling mechanism 220 is provided. Forexample, as illustrated, the catheter body 210 includes, as part of thecooling mechanism 220 a water inlet 221 and a water outlet 222. Cablessuch as RF feedlines or power supply lines 230 are included and may passthrough the body 210, such as to the transducers 230. One or moretransducers 230 are disposed about the catheter body 210. The one ormore transducers may be multi-sectored. In one embodiment each sector240 can be separately powered, such as by a separate wire back to acommon power source. FIG. 1B illustrates a cross-sectional view of thezones defined by the ultrasound emitted from four zones. In oneembodiment, the one or more transducers may be sectored into zonesradially and longitudinally in addition to radially as shown in FIG. 1B.

In one embodiment, single element tubular transducers, such aspiezoelectric devices, including but not limited to ceramic perovskitessuch as lead zirconium titanate (PZT), are used to manufacture theflexible catheter based ultrasound applicator as shown in FIG. 1A. Thetransducer was mounted on a mandril and attached to the extrudedcatheter. The transducer was 1.0-1.5 cm long, with control of heatingenergy in the angular expanse. A coupling balloon was used to cool thetransducer and balloon material was chosen to exhibit minimalattenuation of the ultrasound wave propagating through it. The flexiblemulti-lumen delivery catheter had channels for powering devices andcirculating cooling flow within the cooling balloon. The diameter of thecooling balloon was 7 mm. In one embodiment, the multi-angular sectoreddesign allows a single tubular transducer, to be sub-divided, notmechanically, but electrically, to produce different active sub-elementseach with its own angle of ultrasound power output signal radiation.Further, these transducers may be “stacked” end-to-end to providedifferential control along the length of the catheter in addition toangularly circumferentially around the transducer.

The device designs relate to sectored tubular array devices. As notedabove, planar and focused devices were built and tested, in addition toa bi-sectored tubular design. The bi-sectored tubular design wasexpanded to three angular sectors based on computer simulations andex-vivo (chicken) tissue test results described below. Two examples ofthe bi-sectored array applicators with acoustic coupling—coolingballoons are shown in FIGS. 2A-B.

Ten of the catheters as shown in FIGS. 1A-E, each having with twodifferent angular sectors circumferentially around a single transducerof fixed longitudinal dimension—typically 1 cm to 1.5 cm long, werefabricated for animal model development experiments. For the animalstudies described below, the catheters are dual sectored array catheterof a 70-80° design.

In one embodiment, the applicator may have either bi-sectored arrays ortri-sectored arrays. FIG. 4 illustrates one embodiment of an applicator.Results of electrical performance and applicator efficiency aredescribed further below.

In certain embodiments, such as illustrated in FIG. 4, the applicatormay be manufactured with different size holes through an extruded solidtube (cross-section of extruded portion shown in FIG. 3). The diameterof each extruded hole depends on the purpose such as depending on theelectrical wire diameter used for connecting the RF generator the holes.The extruded tube is different in that it is integral to the assembly,whereas the other method we use to manufacture requires mounting of thetransducer within a segment of the catheter.

As shown in FIG. 1A, a cooling balloon 250 may be provided to cool thetissue exposed to the one or more transducers 230. The cooling balloon250 may be operated by an airline or water line. As discussed furtherbelow, a bladder balloon 260 may be disposed adjacent the end of thecatheter 210 to control the bladder volume and or to provide cooling orother changes to the bladder or other tissue located distal from thecatheter's transducers 230.

In one embodiment, for example as shown in FIG. 4, the device includes atemperature sensor 280 such as a thermocouple to measure temperatureprofile in the treatment zone so that actual dose delivered to thetissue during the treatment real-time will be monitored. In oneparticular embodiment, the temperature sensor is a thermocouple on thetransducer cooling balloon that can monitor the temperature profile, forexample, of the urethra wall during a treatment. In a furtherembodiment, a second temperature sensor (such as a thermocouple) wasattached to the catheter such that it can be deployed to place in thetreatment region during the treatment. The capability to deploy apreformed nitinol needle thermal sensor in one embodiment of anapplicator is shown in FIG. 4.

Degased water was circulated through the catheter for cooling thetransducer during ablation. Degased water was used to minimize thepresence of bubbles. Transducers with four sectors as shown in FIG. 1Cwere used for the experiments. Out of the four sectors, three sectorswere active for the experiments. Specifically zones 1, 2 and 3 were theactive zones. The design allows the use of four sectors when required,and can be extended to a greater or fewer number as required. Threesectors were activated for the present study to demonstrate thesignificant advantage of localization and directional ablation producedwith this technology.

Using electrical impedance and radiation force balance measurements, thecenter frequency and efficiency of each transducer element wasestimated. The center frequency of each individual element was used toexcite the respective element to maximize energy output. Continuous wavemode was used to excite the transducers. Typically transducer centerfrequency ranged from 6.5-7.5 MHz with acoustic efficiency of 50-60%.

In one embodiment, needle thermocouples of type T (Physitemp, NewJersey, USA) were used for monitoring temperature. Each needle was 100±2mm long and 0.82 mm in diameter with 0.1° C. accuracy in temperaturemeasurement with a 0.05 sec time constant. Thermocouples were placed atdifferent distances from the ultrasound applicator and dose wascalculated for each thermal sensor. A custom template was used to insertthe applicator and thermocouples as shown in FIG. 5. The template helpedin registering the location of each thermocouple with respect to theultrasound applicator precisely. The temperature from each thermocouplewas recorded at every 1 second. The thermal dose calculated from thethermocouple temperature-time profile is given by:

$\begin{matrix}{{t_{43} = {\sum\limits_{t = 0}^{t = {final}}\; {R^{({43 - T^{t}})}\Delta \; t}}},\left\{ \begin{matrix}{R = {{0.25\mspace{14mu} {for}\mspace{14mu} T} < {43{^\circ}\mspace{14mu} {C.}}}} \\{R = {{0.50\mspace{14mu} {for}\mspace{14mu} T} \geq {43{^\circ}\mspace{14mu} {C.}}}}\end{matrix} \right.} & (1)\end{matrix}$

where T_(t) is the average temperature recorded by the thermocoupleduring time Δt. The unit of thermal dose is equivalent minutes at 43° C.Typically thermal dose of 240 equivalent minutes at 43° C. can producenecrosis in soft tissue.

Efficiency of the electrical to acoustic power of the ablation catheterswas measured using a pressure force-balance measurement system. Anexample Smith Chart used for impedance analysis for a three sectoredapplicator is shown in FIGS. 10A-C. The conversion efficiency for theablation catheters from electrical input to ultrasound output rangedfrom 55% to 60%, with current designs yielding >50%. An efficiency of50% is considered to be excellent.

Experiments were performed where the applicator was submerged into awater bath and held near the water surface to visualize the acousticpressure wave pattern generated by the output acoustic power from theapplicator. The results are shown in FIGS. 8A-F, where different sectorswere excited to observe different patterns. Insonating a single sectorat 6 W viewed longitudinally demonstrates a distinct collimated patternof the ultrasound field of the sector was observed as shown in FIG. 8(b).

a. Ex Vivo Chicken Study

The purpose of the present study was to investigate the ablation patternobtained using a multi-sectored tubular ultrasonic transducer.Experiments were conducted by activating two and three zones separatelyto investigate the ablation pattern of each case. The treatment wasmonitored by inserting several needle thermocouples into the tissue atvarious distances from the ultrasound applicator. The dose distributionwas determined from the temperature-time profile recorded by each of thethermocouples. The multi-angular ablation pattern created by thetransducer was compared with simulations based on the same designparameters. The simulations were performed by solving the bio-heatequation using finite element method. The experimental and simulationresults are compared with respect to temperature and dose profiles. Itwas observed through visual inspection that one embodiment of themulti-sectored transducer could ablate a specific tissue region ormultiple regions selectively while not damaging the desired surroundingtissue. Simulations results were presented by solving the Penne bio-heatequation using finite element method. The simulation results werecompared with ex vivo results with respect to temperature and dosedistribution in the tissue. Thermocouples located at 15 mm radially fromthe applicator indicated a peak temperature of greater than 52-55° C.and thermal dose of 10³-10⁴ EQ mins at 43° C. Good agreement betweenexperimental and simulation results was obtained.

i. Ultrasound Ablation Ex Vivo Chicken Study

Freshly excised ex vivo chicken breast muscle tissue was ablated usingthe flexible catheter based multi-directional ultrasound applicator. Acustom template to hold the applicator and thermocouples, and a customdesigned tissue holder was used in the experiment as shown in FIG. 5.The custom tissue holder had heating pads to maintain the tissuetemperature at 35-37° C. The tissue was pre-heated to 37° C. using atemperature controlled water bath immediately prior and placed into thecustom tissue holder for the ablation experiment.

A software architecture for treatment planning, control, and monitoringwas developed to communicate with the RF generator, water pump and thethermocouples using a user friendly graphical user interface. Ascreen-shot of the application software is shown in FIG. 26. The waterpump was used to circulate degased water through the cooling balloon.The left column of the screen shown in FIG. 26 was used for displayingthe temperature and the dose versus time graphical information. Theright column was used for displaying the controls and experimentaltreatment parameters used for the study experiments. The buttons at theright column edge of the screen were used for hardware control screensselection. The menu items at the top were used for administrativepurposes such as patient management, file management and other tasks.The software has the functionality to create and execute treatmentplans.

Typically 6-7 W (acoustic) was delivered to the tissue by the ultrasoundapplicator from zone 1 and 2. Acoustic power of 2-3 W was delivered tothe tissue by the ultrasound applicator from zone 3. The lower power forzone 3 enabled to visualize the different ablation pattern intensitythat could be achieved using the proposed technology. The acousticwattage was estimated by considering the system efficiency, transducerefficiency and the transmission through the catheter to the tissue.Water flow rate of 40-50 ml/min was used for each treatment for coolingthe ultrasound ablation transducers in the applicator.

Needle thermocouples were inserted at different distance from theapplicator to monitor temperature profile during treatment.Thermocouples at 5 mm, 10 mm and 15 mm radially from the applicator indifferent zones were inserted using the custom template as shown in FIG.5. The tip of each of the thermocouples was placed at the center of theultrasonic transducer along the vertical axis. The thermocouples weredenoted as Z1-10, Z2-5 etc. The notation for each thermocouple was asfollows: Z1, Z2, Z3 and Z4 refer to the four different zones and thenumber that follows refers to the distance between the thermocouples andthe applicator cooling balloon surface in the radial direction. Forexample Z1-5 refers to the thermocouple placed in zone 1 at 5 mm awayfrom the cooling balloon. All the thermocouples were placed within thefield of the ablation pattern for the respective active sectors.

ii. Finite Element Modeling

The finite modeling similar to known techniques (P. Prakash, V. A.Salgaonkar, E. C. Burdette, and C. J. Diederich, “Hepatic ablation withmultiple interstitial ultrasound applicators: initial ex vivo andcomputational studies,” in Society of Photo-Optical InstrumentationEngineers (SPIE) Conference Series, 2011, pp. 79010R-79010R) was used tosimulate the bio-heat equation with appropriate boundary conditions. Theheat transfer in tissue during ultrasound ablation was modeled usingbio-heat equation given by:

$\begin{matrix}{{{{pc}\frac{\partial T}{\partial t}} = {{{\nabla{\cdot k}}{\nabla T}} + Q_{s} - {{\overset{.}{m}}_{b_{l}}{c_{b_{l}}\left( {\overset{.}{T} - T_{b_{l}}} \right)}}}},} & (2)\end{matrix}$

where ρ is the tissue density, c is the specific heat capacity, T is thetemperature, k is the thermal conductivity, Q_(s) is the acoustic powerdeposited, {dot over (m)}_(bl) is the blood mass perfusion rate, c_(bl)is the specific heat capacity of blood and T_(bl) is the temperature ofblood flow. For the current study the blood perfusion term was neglectedsince there was no blood flow in the ex vivo tissue. The acoustic powerdeposition term is given by:

$\begin{matrix}{{Q_{s} = {2\alpha \; I_{s}\frac{r_{0}}{r}^{{- 2}{\int{\mu \; r^{\prime}{r^{\prime}}}}}}},} & (3)\end{matrix}$

where α is the ultrasound absorption coefficient of the tissue, I_(S) isthe acoustic power intensity at the transducer face, r₀ is the radius ofthe transducer, r is the radial distance from the transducer surface, μis the ultrasound attenuation coefficient and r′ is the radial distancefrom the applicator surface. The values used for the various parametersare tabulate in Table 1.

TABLE 1 Nominal values for tissue properties used in FEM model of thebioheat equation. Parameter Units Value k (thermal conductivity) W m⁻¹K⁻¹ 0.56 c (specific heat capacity) J kg⁻¹ K⁻¹ 3639 α (ultrasoundabsorption coefficient) Np m⁻¹ MHz⁻¹ 4.6 μ (ultrasound attenuationcoefficient) Np m⁻¹ MHz⁻¹ 4.6 r₀ (transducer radius) mm 1.75

Commercial software COMSOL Multiphysics (COMSOL Inc., Burlington, Mass.)was used to simulate the bio-heat model using the finite element method(FEM). For all the simulations, the initial tissue temperature was setto 37° C. The boundary of the tissue was set to a fixed temperature of37° C. A convective heat transfer boundary condition was applied on theinner catheter wall to simulate water cooling given by:

{right arrow over (n)}·k∇T=h(T _(∞) −T),  (4)

where h=4500 W m⁻¹K⁻¹ is the convective heat transfer coefficient andT_(∞)=20° C. is the temperature of the cooling water. An irregular FEMmesh consisting of quadratic Lagrangian elements was used to discretizethe solution space. A sub-millimeter mesh resolution (maximum elementedge length ˜0.5 mm) was employed at the applicator Maximum element edgelength was restricted to 3 mm within the entire computational domain. Anonlinear, implicit solver with variable time steps (0.001<Δt<5 s) wasused to solve the numerical problem. The three-dimensional temperatureprofile was determined using the FEM. Using the FEM results, contourplots of the temperature and dose profiles were constructed forvisualizations.

iii. Results

Experiments were performed where the applicator was submerged into awater bath and held near the water surface to visualize the acousticpressure wave patterns generated by the output acoustic power from theapplicator. The results are shown in FIG. 8, where different angulardirections were excited simultaneously to observe different patterns.Insonating a single direction at 6 W viewed longitudinally demonstratesa distinct collimated pattern of the ultrasound field of the sector wasobserved as shown in FIG. 8 (b). Similarly, the pattern by sonicatingtwo lateral sector and all three directions are shown in FIGS. 8( c) and(d), respectively. Views with three and two active zones are shown inFIGS. 8 (e) and (f), respectively.

Experiments were conducted in ex vivo chicken breast and compared withsimulation results. The input parameters for the FEM model were based onthe experimental treatment parameters and tissue properties. A dualsectored device with transducer length of 10 mm was used for theexperiment and simulations. The first and the second sector had thecenter frequency of 6.64 MHz and 6.7 MHz respectively. The tissue wassonicated for 1-2 minutes with water flow rate of 40-50 mL/min in thecooling balloon.

Acoustic power of 6 W was delivered to the tissue by each of theultrasound ablation transducers in zone 1 and 2. The tissue was exposedto high intensity ultrasound for approximately 1-2 minutes as shown inFIG. 6A. The temperature recorded by the different thermocouple sensorsis shown in FIG. 6( b), where the location of each thermocouple sensorwith respect to the applicator was shown in FIG. 6. The dose calculatedfrom each of the temperature sensor over time readings is shown in FIG.9 (c). The legend for each of the temperature and dose curves shown inFIG. 6 corresponds to the thermocouple labels (Z1-5, Z1-15, Z1-10, Z2-5,Z2-10, Z3-10, Z4-10) shown in FIG. 6. The temperature increasedmonotonically with increase in exposure time and decreased after thepower was turned off. Total dose delivered is in FIG. 6( c). Ablationpattern is shown in FIG. 6( d).

After exposing the tissue either in one or multiple directionallocations, it was examined for gross pathology and visual inspection. Anexample of the gross pathology images are shown in FIG. 6( d). Fromvisual inspection and differentiating treated region with respect todiscoloration, the treatment region was laterally (perpendicular to theapplicator) 15-20 mm long. Thermocouples located at 15 mm radially fromthe applicator showed a peak temperature of 52° C. and thermal dose of6.4×10³ EQ mins at 43° C. Necrosis occurs at 240 EQ mins at 43° C. andhence a minimum radius of 15 mm lesion can be obtained successfully witha 1 min treatment. The uniform discoloration of the treated zoneindicates uniform ablation was obtained within the planned target zonesas shown in FIG. 6 (d).

Additional experiments were performed to form different ablationpatterns as per planned treatment and directly compare with simulationresults. The comparison between the experiments and the simulationresult for delivered acoustic power of 6 W from both the sectors in zone1 and 2 is shown in FIGS. 11A-B. The images of the ablated tissue are inthe axial plane through the central axial plane direction of theapplicator. The comparison between experimental and simulation resultswith respect to temperature and dose profiles spatially for treatmentduration are shown in FIGS. 11 (a) and (b), respectively. The comparisonbetween the experimental and simulation results for the acoustic powerof 4 W and 5 W (equal power applied to both zone 1 and 2) are shown inFIGS. 12( a)-(d). The exposure time was 2 minutes for both the cases. Itcan be observed that more power produced a larger ablated region. Goodcorrelation was observed between gross tissue pathology and both thetemperature and dose contours. The region of tight coagulation seen onphotographs of ablated tissue corresponds well with 60° C. contourpredicted by the models.

Experiments were also performed for simultaneous activation of threeangular directions. Acoustic powers of 7 W, 7 W and 3 W were deliveredto the tissue by the sectors in zones 1, 2 and 3, respectively. Thecentral zone was excited with lower power purposefully to obtain thedifferent treatment pattern. The experimental and simulation results fortemperature and dose are shown in FIGS. 13( a) and (b), respectively.The yellow dotted lines indicate the plane of tissue cut and the curvedarrow shows that the left part of the tissue was flipped open tovisualize the ablated region clearly. The simulation results aredisplayed as contours and clearly demonstrate good agreement with theexperimental results. It can be observed that zones 1 and 2 have moreradial depth of penetration than in zone 3. This is due to the designeddifferential power delivered to the tissue of those treatment zones.

All the experimental results show very good agreement with thesimulation results. The results clearly demonstrate that the tissue inzone 4 was not at all treated or damaged. In all the experiments, thetissue in the deactivated zones clearly showed no thermally induceddamage. Therefore, the current technology can be used efficiently toablate planned regions while sparing nearby veins/vessels. Such minimalinvasive thermal therapy procedure may not be feasible with othercurrently available technologies.

Experiments were performed to investigate the feasibility of usingdirectionally sectored tubular ultrasound transducer to createmulti-angular ablation patterns in tissue. The proposed technology hasachieved accurate directional acoustic energy to the planned locationswithout damaging the surrounding tissue. The experimental results werecompared with simulation results for verification. The simulation wasperformed using commercially available finite element method software tosolve the bio-heat equation with appropriate boundary conditions. Theexperimental results demonstrated that the directionality and shape ofthe ablation zone can be controlled using catheter based high intensitymulti-directional ultrasound transducers. The transducers enabledcreation of desired ablation patterns without damaging the nearby tissueand verified through both gross pathology inspection and measured data.

Ex vivo chicken breast tissue samples was used here to eliminate theeffects of blood flow for this feasibility and preliminary study. Weplan to conduct future experimental studies using the proposed techniquefor treating in vivo tissues and study the effects of blood flow on theresults obtained as compared with the results in this study. For the invivo study we plan to include the blood perfusion terms into thebio-heat equation model and solve using finite element methods. Moreexposure time or higher acoustic power may be needed for in vivo tissuecompared to time needed in this study to achieve similar treatmentvolume in both cases since the blood flow will act as a coolant duringthe in vivo treatment. Parametric characterizations of this dependencywill be studied and developed for future treatment use.

2. Treatment Applications

One embodiments relates to methods for treatment. Certain embodiments ofthe device described above are able to create treatment zones ofdifferent shapes according to the anatomy of the patient by controllingthe power deposition in each angular sector of the multi-sectoredtransducer. Therefore, physiological issues such as disease orconditions, for example SUI as further discussed below, can be treatedusing the concept of personalized medicine. The anatomy of every humandiffers from person to person and the various embodiments will beconsidering such variations to deliver optimized treatment according tothe anatomy. For some applications, the complete treatment time is 2minutes in a single placement of applicator—something not available withthe current thermal therapy procedures. Every delivery occurs in onlyone step (not multiple locations/insertions), reducing the operatorvariability during procedure. Such controllable thermal ablationtechnique does not presently exist for many thermal treatments, such asthermal treatment of SUI. Unlike other thermal therapies such as RFA theproposed technology does not require to pass electric current passedinto the patient's tissue, isolating the patient electrically. Moreover,various embodiments are a noninvasive procedure, with no needles orincisions.

3. Stress Urinary Incontinence Treatment

The feasibility of using a catheter based ultrasound transducer systemwas shown above with regard to ex vivo use in chicken. However, one invivo application of importance is the treatment of Stress UrinaryIncontinence (SUI). Stress Urinary Incontinence (SUI) is unintentionalloss of urine prompted due to physical movement or activity such ascoughing, sneezing or heavy lifting which exerts pressure on thebladder.

One technique described herein uses high intensity directionalultrasound ablation to achieve superior results remodeling theendopelvic fascia. The primary advantage of high intensity ultrasound isthat it is more penetrating and controllable than RF, and may affectthermal remodeling of the collagenous structure of the endopelvic fascia(noninvasively) by propagating acoustic energy through the urethra anddeep into the endopelvic fascia. The proposed procedure eliminates theuse of any incision for the thermal ablation and can produce the hammockeffect of a sling.

The approach requires urethral insertion of a catheter-based ultrasoundapplicator with a multi-sectored tubular radiator, such as describedabove. Acoustic energy is targeted specifically to the endopelvic fasciaand connective tissue at the lateral aspects of the urethra without theneed for an incision. The resultant thermal remodeling of thecollagenous structures in the endopelvic fascia will restore thestructure to a more normal anatomy, without damaging the tissuestructures of the urethra or vagina. It is believed a multi-sectoredtransurethral ultrasound applicator can generate penetrating andselective thermal therapy while urethral mucosa is protected withcooling. This provides a minimally-invasive framework for targeting theendopelvic fascia, more accurately and effectively than current RFapproaches, and less-invasive than surgical techniques.

As described in further detail, one embodiments relates to acost-effective, non-invasive and feasible approach for thermal treatmentof SUI using transurethral high intensity ultrasound. All currentsurgical interventions involve incisions or needle insertions throughthe urethral wall or vaginal wall, in some instances depositing orplacing implants.

In one embodiment, modification of the endopelvic fascia may be achievedin a simple, non-invasive manner with high intensity concentratedultrasound via a transurethral approach. There currently exists clinicalevidence that heating the pelvic floor and/or tissue surrounding thebladder neck to produce shrinkage to stabilize the urethral structurehas a significant and positive clinical effect. Initial laboratorytesting for this application has been performed which indicates that thecatheter based ultrasound technology described above can create lesionsof the appropriate dimension to affect that change.

This approach will (1) selectively heat the anatomic structure(endopelvic fascia) to be treated (mid-urethra); (2) map the treatmentfocal depth and focal zone; (3) apply acoustic energy to raise thetemperature of selected tissue regions within the endopelvic fascia to55° C. to 75° C. for a short time period to affect immediate tighteningand remodeling (stimulating fibroblasts) of the collagenous structure ofthe endopelvic fascia. The approach has the capability of accuratelydeliver acoustic energy to endopelvia fascia with controllabledirectivity and directionality.

i. Computer Modeling

In one embodiment, a treatment for SUI is provided. One method oftreatment for SUI uses direction ultrasound ablation. Computersimulations were run that simulated using the three-dimensional (30)finite element model (FEM). The anatomical geometry from representativepatients was used to build the 30 models and used for constructing theFEM mesh. The simulation methods were as follows:

-   -   Anatomical model geometry: Serial axial MRI scans from        representative patient cases were segmented using a contouring        software program to delineate anatomical structures such as        vaginal wall, urethral mucosa, bladder, etc. as shown in FIG.        15A-C.    -   Applicator: The applicator was assumed to have a single tubular        transducer (diameter=3.5 mm), with three active sectors. The        side sectors were assumed to have an angle of 90°, while the        central sector aimed towards the vaginal wall was assumed 62°.        The cooling balloon was assumed to have a diameter of 7 mm. The        applicator was placed along the urethral axis with the        applicator tip was placed 10-12 mm proximal to the bladder neck.    -   Biothermal model: Pennes equation was assumed to model heat        transfer. Blood perfusion was assumed to be homogeneous in        tissue and was reduced to zero where the local temperature was        raised above 55 ′C. Cooling water temperature was assumed to be        20 ′C, and the cooling coefficient was set to 4500 W/m²/K.        Models were solved using Comsol 3.5a (Comsol Inc.)    -   Acoustic model: A geometric approximation was used to model        acoustic intensity which was assumed to be inversely        proportional to the radial distance from the applicator (decay        from the surface intensity with a factor of 1/r). The transducer        frequency was set to 7 MHz. Nominal value of acoustic        attenuation was set to 46 Np/m, and was doubled for vaginal        wall. Temperature dependent changes in attenuation were ignored.

The numerical model was meshed by using finite elements to discretizethe solution space and appropriate boundary conditions were imposed.Three-dimensional temperature profile was estimated using the FEM. Usingthe FEM results, contour plot of the temperature profile followed by thethermal cloud was constructed for visualizations. The flow for theseprocesses is shown in FIG. 16. A nonlinear, implicit solver withvariable time steps was used to solve the ablation problem.

ii. Results: Patient Specific Simulations

(1) Patient 1

Using FEM, specific absorption rate (SAR) was estimated for two andthree sectored transducers as shown in FIG. 17. It is believed that thethree sectored transducer may be helpful to treat different tissuethickness at different directions in a single ablation. The simulatedtreatment patterns (temperature isotherms) using two and three sectoredtransducers are shown in FIGS. 18 and 19, respectively. The two sectoredtransducer had each sector of 90° and the three sectored transducer hadtwo 90° sectors and the middle sector was 60°. The treatment patternswere shown at time step 3 mins and 5 mins for both transducer types. Forboth the simulation acoustic power of 4.7 W were used for the largersectors and 1.2 W was used for the middle sector on the three sectoredtransducer. The temperature clouds for each of the cases are shown inFIGS. 18 and 19.

The three-dimensional temperature distribution for a representativepatient anatomy is shown in FIGS. 20A-D using a two sectored applicator.The simulated results showed the different regions such as necrotic andcoagulated tissue for the different treatment cases. The necrotic,coagulated and safety tissue regions were identified using thetemperature profile given by the FEM results. The simulation resultswere also shown for transducer of length 10 mm and 14 mm. The differentlength of the transducer may be helpful for treating patients withshorter or longer urethra.

(2) Patient 2

The second patient's anatomy is shown in FIG. 1523. Hence, power levelsto the center sector were varied (FIG. 22.). The simulated treatmentresult is shown in FIG. 21. It was observed that by varying the power inthe central sector of a three sectored transducer changed thepenetration depths for the treatment.

iii. Results: Comparing Models and Ex Vivo Experiments

Experiments were conducted in ex vivo chicken breast maintained between33-35 ′C and compared with simulation results. All the experimentalparameters were used as input parameters for the FEM model. A dualsectored device with transducer length of 10 mm was used for theexperiment and simulations. The first and the second sector had thecenter frequency of 6.64 MHz and 6.7 MHz respectively. The tissue wassonicated for 2 minutes with water flow rate of 45 mUmin in the coolingballoon. The chicken breast tissue was used for experimentalverification and validation. The same tissues with all the appropriateacoustic and thermal properties characteristics for these tissues werealso modeled using the computer acoustic and thermal models to predictthe thermal heating distributions for the exact tissue properties andgeometries that we studied experimentally. This provided clear evidenceof corroboration between actual experimental results and representativetheoretical models which have previously been verified in othertissues—e.g. prostate.

The comparison between the experiments and the simulation result fordelivered acoustic power of 6 W from both the sectors is shown in FIGS.11A-B. The images of the ablated tissue were along the axial planethrough the central axial plane through the applicator. The comparisonbetween the experimental and simulation results for the acoustic powerof 4 W and 5 W are shown in FIGS. 12 (a)-(d). Good correlation wasobserved between tissue damage and temperature and dose contours. Regionof tight coagulation seen on photographs of ablated tissue correspondswell with 60″C contour predicted by the models.

iv. Results: Parametric Study

Patient case #1 was utilized as representative model geometry. Aparametric study was carried out using the information for patient one.The Input Parameters were Perfusion=0.5-5.0 kg/m³/s, Time=0-10 min, sidesector acoustic power=2-8 W, central sector acoustic power=0-3 W,Transducer length=14 mm. Acoustic power settings of 6, 6, 3 W were foundto produce clinically relevant thermal ablation and hence used as arepresentative case to show radial and longitudinal temperature/thermaldose profiles. Radial and longitudinal dimensions for safety margins(T=45° C., EM43° C.=10 min), necrosis (52° C., 240 min), and tightcoagulation (60° C., 1000 min) have been included. For the parametricstudy, findings from the tables can be summarized as:

-   -   For acoustic power of 2, 2 0 W, 10 min exposures may be required        to treat radial distances in excess of 10 mm.    -   With 6, 6, O and 4, 4, O W, it may be possible to treat 10-15 mm        radially within 2-5 min. Safety margins may extend 5 mm beyond        this range.    -   With 8, 8, 0 W, targets can be treated within 2 min, but high        maximum temperatures exceeding 90° C. were estimated.    -   Heating due to side and center sectors are decoupled to a large        extend and radial or longitudinal heating due to the side        sectors is not significantly impacted by powering the center        sector to 0-3 W.    -   With 2 W acoustic power to the center sector, 0-12 mm radial        depths can be treated.    -   Excised pig GU tract tissue experiment

Excised pig GU tract were obtained from the University of Illinoisslaughter house to conduct the preliminary experiment before conductingthe in vivo experiment. The main aim of the tissue experiment was toverify the feasibility of inserting the treatment catheter through theurethra for treatment, and also get familiar with the GU tract anatomy.The length of the urethra in the excised pig GU tract used for thelaboratory experiment was approximately 11 cm.

The tissue was treated at three different locations at mid-to-higheracoustic power levels to deliver greater thermal dose. This acousticpower range is typically from 6 to 10 acoustic watts, depending upontarget volume and thermal dose target desired. The high acoustic powerlevels were used purposely so that the treatment may be identifiedvisually. The second goal of the experiment was to determine if thedeployed thermocouple would adequately penetrate through urethral wallto measure temperature of the treatment region. For the experiment thetissue was mounted on a custom GU tract holder. The semi-cylindrical GUtract tissue holder helped to mimic in vivo intact position. After thetreatment the tissue was dissected along the vaginal muscular tube suchthat the vaginal wall was visible for inspection. The three treatmentregions were clearly visible by visual inspection.

The acoustic power delivered to each of the treatment locations istabulated in Table 2. The duration of each power was varied to observethe effects on peak temperature and applied thermal dose. The peaktemperature and peak cumulative dose of 72 ′C and 9.1×10⁹ EQmins wasobserved for the Treatment 2, which showed largest treated region andmaximum tissue damage out of the three treatments. The correlationbetween the dissected tissue images and thermometry recorded by thethermocouples were in good agreement.

TABLE 2 Excised pig GU tract on the tissue holder after treatment.ACOUSTIC DURA- PEAK CUMM POWER TION TEMP DOSE EXP LOCATION (Watts)(min:sec) (° C.) (mins) Treatment Near bladder 3-3-3 0:38 40 0 1 neck6-6-6 1:53 65 5.6 × 10¹ Treatment Intermediate 3-3-3 0:35 42 0 2 6-6-50:34 64 1.2 × 10¹ 6-6-6 0:50 72 9.1 × 10!:| Treatment Near urethra 3-3-52:00 57 2.4 × 10° 3 opening

B. In Vivo Animal Model Studies

Further in vivo animal studies were completed. For purposes of testingthe described devices ability to treat SIU, pigs were initially utilizedfor testing and more accurate SUI testing was done using the ewe due toits closer anatomy with regard to urethra length compared to humans.

i. 1. Pigs Used for Initial In-Vivo Animal Model for Device Evaluationand Applicator Design Feedback

In vivo experiments were conducted to treat SUI using porcine as theanimal model. A total of 6 pigs were used for the study. Theexperimental protocol used for all the experiments is as follows:

-   1. Anesthetize the pig-   2. Insert Transvaginal imaging probe to locate and measure the    length of the urethra-   3. Remove the imaging probe-   4. Use the measurement obtained from ultrasound images in Step 2 to    mark the catheter accordingly-   5. Use a speculum and insert the catheter under illumination-   6. Using the speculum carefully place the catheter according to the    marking made on the catheter in Step 4; remove speculum-   7. Confirm catheter is oriented correctly in rotational angle-   8. Once the catheter is placed accurately, deploy the thermal needle    for temperature measurement in the treatment zone-   9. Start the treatment    -   Monitor temperature and dose in the treatment zone    -   Adjust the input acoustic power accordingly-   10. After the desired temperature and dose is achieved stop the    treatment and remove the catheter

The animal was anesthetized and bought to the surgery suite on astretcher and placed on the surgery table. The health condition of theanimal was constantly monitored in terms of heart beat and bloodpressure until the end of the experiment. The treatment was conducted bya senior veterinarian and the animal health conditions were monitored bytwo other junior veterinarians. No significant health issues wereobserved in any of the experiments during the treatment. Afterconducting the first experiment using a young pig it was realized thatthe young pigs (that did not gave birth to piglets) did not had awell-developed reproductive and urinary organs. Thus the length and thediameter of the urethra were not comparable to the human anatomy. Thusfor the rest of the experiments older pigs were used. The weight of thepigs ranged from 160-200 lbs and was 1-2 years old and gave birth topiglets several times.

The experiments with the pigs helped in evaluating the applicator designand treatment protocol. At the beginning of the in vivo study, thetreatment was given to the animal by placing the ultrasound imagingprobe in the vagina and the treatment applicator in the urethra. Thisprocedure was followed such that real time ultrasound imaging mayprovide information about treatment. In this procedure it was observedthat the treatment tissue thickness was decreased significantly due tothe pressure exerted on the tissue between the vaginal tube and urethrafrom the ultrasound imaging probe. In this setup thermocouple sensorswere embedded on the ultrasound imaging probe to record the temperaturerise at the vagina wall during the treatment.

After feedback from the experiment two thermocouple sensors were placedfrom the applicator itself as shown in FIG. 4. In addition a measurementsensor may be deployed from the catheter wall into the tissue for directmeasurement of the thermal dose in a portion of the target zone oftreatment for conformation.

As a result of the pig testing results, the procedure was modified touse the ultrasound imaging probe to estimate the length of the urethrabased on the ultrasound images. An ultrasound image of the vagina walland the urethra by inserting the transurethral ultrasound imaging probe(BPL 9-5/55, Sonix Touch, Ultrasonix, Canada) through the vagina isshown in FIG. 23. The target region for the treatment is indicated inthe FIG. 23.

Using the ultrasound images the treatment catheter was marked andinserted into the urethra for treatment. The treatment parameter wascontrolled using software tools. After each experiment the animal wassacrificed and GU tract was dissected and removed from the animals.First the gross pathology analysis was done followed by fixing thetissue in formalin for further detailed histopathological analysis. Thelength of the urethra ranged from 12-15 cm.

The tissue was further dissected along the vagina and urethra foranalysis. After dissecting the tissue was submerged intotriphenyltetrazolium chloride (TTC) for staining. The TTC stajn makesthe treated region visually more visible than the normal tissue foreasier visual identification of the treatment region. Typicallytreatment was delivered near the bladder neck, near the urethra openingand intermediate region between the bladder neck and urethra opening.The dissected tissue after treatment is shown in FIGS. 24( a)-(b), wherethe tissue discoloration in the treatment zone is easily identified. Theapplicator was placed to verify the treatment location based on themarking on the applicator. Peak temperature and peak dose delivered were57 C and 12×104 mins of equivalent dose respectively were observed foras shown in FIGS. 24( c) and (d).

Although pigs do not serve as a perfect analog to human pathology, theexperiments aided experience with proposed technique and refining thetechnology in terms of hardware, experimental parameters and softwaredevelopment. The experiment also helped to learn the way the tissuesneed to be dissected for gross pathology and histological examinations.The experiment also helped to define the range of acoustic power neededto ablate the desired treatment regions as needed.

ii. Ewe as the Animal Model

The length of the urethra in the ewe is within the range of the lengthof the urethra in human. Hence ewes were used for the purpose ofperformance evaluation and determination of tissue effects and thermaldose assessment. A total of 6 ewes were used for the study. Out of these6 ewes, one was a very young ewe used for the first experiment due tothe unavailability of the older ewes.

The experimental protocol with minor modifications compared with theprotocol used for the pig experiment is as follows:

-   -   1. Anesthetize the ewe    -   2. Insert Transvaginal imaging probe to locate and measure the        length of the urethra and check if bladder is empty/full    -   3. If bladder is full then drain the urine using a drainage        catheter    -   4. Remove the imaging probe    -   5. Use the measurement obtained from ultrasound images in Step 2        to mark the catheter accordingly    -   6. Use a speculum and insert the catheter under illumination    -   7. Using the speculum carefully place the catheter according to        the marking made on the catheter in Step 4    -   8. Confirm catheter is oriented correctly in rotational angle    -   9. Once the catheter is placed accurately, deploy the thermal        sensor needle in target tissue for temperature measurement in        the treatment zone    -   10. Start the treatment        -   Monitor temperature and dose in the treatment zone        -   Adjust the input acoustic power accordingly    -   11. After the desired temperature and dose is achieved stop the        treatment and remove the catheter    -   12. Tie tissue using suture at each treatment location to assist        pathologist with identification of treatment location for slide        preparation

The ewe was first anesthetized before the treatment and laid on thesurgery table by the stomach keeping the hind limbs hanging from thetable. One senior veterinarian along with several personnel was involvedto anesthetize the ewe. The condition of the ewe was constantlymonitored by two other junior veterinarians during the entire procedureuntil sacrificing the ewe. During the treatment no significant healthproblem with respect to pulse rate, blood pressure and bleeding wereobserved in the ewe in all the experiment. The ewes usually weighed40-60 Kgs and 3-4 years old. The ewes that had given birth several timeswere chosen for the study.

A speculum was used to view the urethra opening for visual inspectionand help in inserting the catheter easily. Before every treatment thebladder is emptied out using a drainage catheter. A full bladder maystretch the urethra due to weight of the urine in the bladder whichresults in elongated tissue. To help having relaxed tissue in the GUtract the bladder was emptied before the experiment.

The urethra was imaged by inserting a transurethral ultrasound imagingtransducer (BPL 9-5/55, Sonix Touch, Ultrasonix, Canada) through thevagina of the ewe. The ultrasound imaging system is an FDA approvedsystem. Ultrasound image of the vaginal wall and the urethra is shown inFIG. 25. The tissue between the vagina wall and the urethra is thetreatment region. The ultrasound images helped in measuring the lengthof the urethra which ranged from 5-7 cm in the ewes.

The treatment catheter was marked based on the ultrasound images.Typically in each experiment tissue near the bladder neck, center of theurethra and near the urethra opening were treated.

The treatment is controlled by using software tools. An example screenshot of the treatment screen is shown in FIG. 26, where ultrasoundimaging and treatment control can be done simultaneously. The left panelof the treatment screen is dedicated for ultrasound imaging, imagecontouring, three-dimensional and dose display. Temperature profile ofthe deployed and balloon thermocouples and it respective doses are shownin the center column of FIG. 26. The doses are shown in terms ofequivalent minutes at temperature of 43° C. The bottom right panelcontrols the RF generator where user can input the required parametersin terms of input frequency and desired output acoustic power. The RFgenerator panel displays the forward and backward acoustic power to theapplicator, delivered acoustic power to the tissue and efficiency ofeach sector in the applicator. Since each sector were individuallycontrolled allowed to apply different acoustic power to different tissuetreatment regions. The top right panel display show several experimentalparameters and controls for the water pump and the RF generator. Theinformation such as pump flow rate of 45 mUmin is displayed as shown inFIG. 26. Robust and sophisticated software architecture is used tomanage physician, patient and individual treatment information efficientand accurately. This administrative panel can be viewed by selecting theAdministrative tab shown at the top of FIG. 26. The software providesvery useful and critical information that can help to treat the patientsuccessfully.

Immediately following each experiment, gross pathology analysis weredone. The veterinary surgeon carefully removed the portion of the GUtract for gross pathology examination. The length of the urethra wasapproximately 6 cm. After treatment the tissue in the treated region wasstiffer than the surrounding tissue. Minor to major discoloration wereobserved in the treatment regions.

By dissecting the vagina and urethra, further gross pathologicalinvestigation were conducted in each experiment. The top view of thetreatment region and the vagina wall are shown in FIGS. 27A-B,respectively. After dissecting, the tissue was submerged into TTC forstaining. The three treatment regions specifically near the bladderneck, approximately center of the urethra and near the urethra openingare marked by circle in FIG. 27( a). For shorter urethral lengths, twolocations along the urethral length were treated. The darker spot ontreatment region 2 was due to insertion of the deployed needle duringthe treatment to monitor tissue temperature in the treatment region inreal time. No damage in the interior of the bladder was observed for allthe experiments also shown in FIG. 27( a). The vagina tube was dissectedto investigate for any damage on the vagina wall. Similar to bladderinterior, no tissue damage regions were observed on the vagina wall asshown in FIG. 27( b).

The thermometry data and the delivered acoustic power on each of thethree sectors of the applicator (denoted Ch. 1, 2 and 3) for the grosspathology images shown in FIGS. 27A-B are shown in FIG. 328. Thedelivered acoustic power for each of the sector and time duration wastabulated in Table 3. All the treatment lasted for 3-3.5 minutes at anaverage acoustic power of 7, 7 and 3 watts to channels 1, 2 and 3respectively.

TABLE 3 Experimental parameters used for each treatment region. TOTALACOUSTIC DURATION DURATION EXP LOCATION POWER (Watts) (min:sec)(min:sec) SUI1 Near bladder 6-6-3 0:00-1:20 1:20 neck 7-7-3 1:21-3:302:09 SUI2 Intermediate 7-7-3 0:00-3:02 3:02 SUI3 Near urethra 7-7-30:00-2:00 2:00 opening 8-8-3 2:01-3:17 1:17

Histology pathology analysis was performed on a subset of specimensafter the experiment The treatment region were first cut into thinslices of 1-2 mm thickness and submerged into formalin. Generally threeto four histopathology slides were made from each treatment zone. Tissuesections were stained with hematoxylin and eosin (H&E). This stainingprocess involves the application of hematoxylin which colors the nucleiblue and the rest of the structure such as cytoplasm, blood cells isstained at different shades of red and pink. For example blood cells arecolored as red in the histology slides. The microscopic slides wereexamined by pathologists.

iii. Ewe as a Survival Study Animal Model

Initial survival study was conducted on two old ewes that had givenbirth to lambs several times before the start of the experiment. Boththe ewes weighted 66 Kgs approximately. The experimental protocol withminor modifications compared with the previous ewe experiments is asfollows:

-   -   1. Anesthetize the ewe    -   2. Insert Transvaginal imaging probe to locate and measure the        length of the urethra and check if bladder is empty/full    -   3. If bladder is full then drain the urine using a drainage        catheter    -   4. Remove the imaging probe    -   5. Use the measurement obtained from ultrasound images in Step 2        to mark the catheter accordingly    -   6. Use a speculum and insert the catheter under illumination    -   7. Using the speculum carefully place the catheter according to        the marking made on the catheter in Step 4    -   8. Confirm catheter is oriented correctly in rotational angle    -   9. Once the catheter is placed accurately, deploy the thermal        sensor needle in target tissue for temperature measurement in        the treatment zone    -   10. Start the treatment        -   Monitor temperature and dose in the treatment zone        -   Adjust the input acoustic power accordingly    -   11. After the desired temperature and dose is achieved stop the        treatment and remove the catheter    -   12. Transfer the ewe to the recovery room and monitor the animal        for any bleeding. It is a good sign if the animal urinates        within 1-2 hours after the recovery.    -   13. Monitor the animal status for the next 4-5 weeks before        sacrifice    -   14. At necropsy, examine gross pathology tissue changes and        prepare samples for histology

Specifically Steps 12-14 in the above protocol were different comparedto the previous protocol used for the non-survival ewe experiments. Theanimal preparation and treatment procedure were identical to thenon-survival ewe experiment as described above. Two treatment locationswere assigned for each of the two ewes. An example of the temperatureprofile, dose and delivered acoustic power are shown in FIGS. 32A-C.Both treatment for the first ewe demonstrated desired thermal dose(10⁴-10⁵ DEQ mins) and peak temperature rise of 55-60″C. For the secondewe both the treatments showed significant thermal dose and temperatureprofile. The transducer position in the second treatment location of theEWE-200 exhibited much higher temperature/dose in shorter time in targettissue zone outside of urethra; however, note that urethral temperaturedid not exceed 37″C. Higher target temperature most likely due toreduced blood flow in treated tissue region at that position in urethra.

Both the ewes were frequently monitored for 24 hours after treatment anddid not show any urethral bleeding or stricture. The ewes urinated asnormal within an hour following the treatment. A series ofhistopathologic studies of the treated tissues were performed and theslides revealed that the target regions received thermal dose sufficientto cause changes in collagen structure and tissue viability.Non-targeted regions were not affected.

C. Discussion

Various levels of applied acoustic power were used to conduct aparametric study to determine the optimal acoustic power needed to risethe tissue temperature to 50-60° C. which is the desired temperature forthe treatment. A thermal dose of greater than 240 equivalent minutes at43° C. triggers the cells initiate the denaturing process in thecollagen. A thermal dose of 10⁵-10⁶ equivalent minutes at 43° C. was themain goal for the treatment. Considering all the 14 experimentsperformed in ewes, the mean, maximum and minimum acoustic powerdelivered to the tissue from Channels 1, 2 and 3 are shown in FIG.48A-C. Mean acoustic power levels of 7 W, 7 W and 3 W were delivered tothe tissue by Channels 1, 2 and 3 respectively. It has been observedthat this mean acoustic power settings showed good treatment region ingross pathological examination with stiffer tissue in the treated regioncompared to the untreated surrounding tissue.

The mean, maximum and minimum temperature and dose recorded by thedeployed thermocouple and thermocouple on the balloon are shown in FIGS.31A-B respectively. The mean temperature recorded by the deployedthermocouple ranges were from 56-58° C. as shown in FIG. 31( a), whichwas the desired temperature rise required to trigger denaturing thecollagen fibrils. Mean temperature of approximately 38-40° C. wasrecorded by the thermocouple on the balloon during the treatment asshown in FIG. 31.(b). The mean, maximum and minimum dose recorded by thedeployed range falls within the desired range of 10⁵-10⁶ equivalentminutes of 43° C. as shown in FIG. 31( b). Since the temperaturerecorded by the thermocouple on the balloon was less than 43° C., nodose were recorded for all the experiments as shown in the FIG. 31( b).Two representative experimental results and delivered acoustic power andexposure durations are tabulated in Table 4.

TABLE 4 Experimental parameters and analysis for all ewe experiments.PEAK CUMM POWER DURATION TEMP DOSE EXP LOCATION (Watts) (min:sec) (C.)(mins) EXP DATE: 10-10-2012 SU11 Near bladder 6-6-3 1:20 53 4.90 × 10<:neck 7-7-3 2:09 55 7.16 × 10; j SUI2 Intermediate 7-7-3 3:02 50 2.77 ×10 SUI3 Near urethra 7-7-3 2:00 53 7.40 × 10<: opening 8-8-3 1:17 614.65 × 10⁴ EXP DATE: 10-03-2012 SUI1 Near bladder 5-5-2 1:07 44 0.4 neck6-6-3 2:28 56 2.57 × 10³ SUI2 Intermediate 1 6-6-3 3:30 57 3.80 × 10³SUI3 Intermediate 2 7-7-3 2:40 54 9.93 × 10² 7-7-4 1:21 59 1.71 × 10⁴SUI4 Near urethra 8-8-3 0:40 58 1.46 × 10⁴ opening 7-7-3 0:32 57 2.40 ×10⁴ 8-8-3 1:18 57 4.68 × 10⁴ 9-9-3 0:30 59 5.76 × 10⁴

d. Animal Model Studies Summary

Following the results of the animal study, the optimal treatmentparameter ranges for acoustic power, time, maximum temperature, andthermal dose determined based upon a total of 14 Ewe treatment caseswere determined for one embodiment.

With respect to the use of substantially any plural and/or singularterms herein, those having skill in the art can translate from theplural to the singular and/or from the singular to the plural as isappropriate to the context and/or application. The varioussingular/plural permutations may be expressly set forth herein for thesake of clarity.

The foregoing description of illustrative embodiments has been presentedfor purposes of illustration and of description. It is not intended tobe exhaustive or limiting with respect to the precise form disclosed,and modifications and variations are possible in light of the aboveteachings or may be acquired from practice of the disclosed embodiments.It is intended that the scope of the invention be defined by the claimsappended hereto and their equivalents.

What is claimed is:
 1. An apparatus for ultrasound treatment comprising:a catheter, at least one transducer in communication with the catheterand comprising a plurality of transducer zones; a cooling system forcirculating through the catheter to cool the apparatus and acousticallycouple the at least one transducer to a tissue. wherein the each of thetransducer zones is independently operable.
 2. The apparatus of claim 1,wherein the plurality of transducer zones comprise a first transducerzone, a second transducer zone, and a third transducer zone
 3. Theapparatus of claim 2, wherein the plurality of transducer zones comprisea first transducer zone, a second transducer zone, a third transducerzone, and a fourth transducer zone.
 4. The apparatus of claim 3, whereinthe at least one transducer is a tubular transducer having a pluralityof sectors.
 5. The apparatus of claim 4, further comprising a coolingballoon disposed about the at least one transducer and in communicationwith the cooling system.
 6. A method for treating tissue comprising:insert a multizone ultrasonic catheter to a desired depth relative tothe tissue; orient the catheter with respect to rotational angle;activate one or more zones of the multizone ultrasonic catheter, whereinthe activated zones are selected based upon the treatment zone; monitortemperature and ultrasound dose in the treatment zone; after a desiredtemperature and dose is achieved deactivate the multizone ultrasoniccatheter.
 7. The method of claim 6, further comprising inserting atransvaginal imaging probe.
 8. The method of claim 6, further comprisingdeploying a thermal sensor in the tissue for temperature measurement ina treatment zone;